Cited by 464Adipokines, Inflammation, and Metabolic DiseasesAdipose Tissue and MetabolismCardiovascular Disease and Adiposity

Impaired adipogenesis and dysfunctional adipose tissue in human hypertrophic obesity

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Hammarstedt, Ann, Gogg, Silvia, Hedjazifar, Shahram, Nerstedt, Annika, Smith, Ulf·2018·Physiological Reviews

Abstract

The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or differentiating available precursor cells. When inadequate, this leads to a hypertrophic expansion of the cells with increased inflammation, insulin resistance, and a dysfunctional prolipolytic tissue. Epi-/genetic factors regulate SAT adipogenesis and genetic predisposition for type 2 diabetes is associated with markers of an impaired SAT adipogenesis and development of hypertrophic obesity also in nonobese individuals. We here review mechanisms for the adipose precursor cells to enter adipogenesis, emphasizing the role of bone morphogenetic protein-4 (BMP-4) and its endogenous antagonist gremlin-1, which is increased in hypertrophic SAT in humans. Gremlin-1 is a secreted and a likely important mechanism for the impaired SAT adipogenesis in hypertrophic obesity. Transiently increasing BMP-4 enhances adipogenic commitment of the precursor cells while maintained BMP-4 signaling during differentiation induces a beige/brown oxidative phenotype in both human and murine adipose cells. Adipose tissue growth and development also requires increased angiogenesis, and BMP-4, as a proangiogenic molecule, may also be an important feedback regulator of this. Hypertrophic obesity is also associated with increased lipolysis. Reduced lipid storage and increased release of FFA by hypertrophic SAT are important mechanisms for the accumulation of ectopic fat in the liver and other places promoting insulin resistance. Taken together, the limited expansion and storage capacity of SAT is a major driver of the obesity-associated metabolic complications.

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Crossref · 10.1152/physrev.00034.2017

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  • With overweight and obesity, adipocyte hypertrophy results in tissue hypoxia and mechanical stress which trigger immune cell invasion and activation.

    “Whereas hyperplasia is regarded as metabolically protective, adipocyte hypertrophy results in tissue hypoxia and mechanical stress which trigger immune cell invasion and activation [18].”

    From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [18]

    Figure 5 links hypertrophic expansion to excessive hypoxia, and section V describes how hypertrophic adipocytes promote macrophage recruitment and inflammation. The paper also links hypoxia to inflammatory pathways, but the passages do not identify mechanical stress as a trigger of immune-cell invasion or activation; Figure 5 says metabolic stress instead. Section V cautions that not all obese people develop chronic inflammation. (LLM, conf=0.86)

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  1. 10.1093/ansci/82.3.925 · DOI

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Authors
Hammarstedt, A., Gogg, S., Hedjazifar, S., Nerstedt, A., & Smith, U.
Affiliations
University of Gothenburg (SE)
Venue
Physiological Reviews
Published
2018-10-01
Volume
98
Issue
4
Pages
1911-1941
ISSN
  • 0031-9333 (ISSN-L)
  • 1522-1210
OpenAlex
W2886159477
Cited by
462
References
336
Citations by year
2026: 48 · 2025: 54 · 2024: 73 · 2023: 68 · 2022: 79 · 2021: 54 · 2020: 61 · 2019: 22 · 2018: 2
FWCI
4.98
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Physiological Reviews (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • The Swedish Research Council, Sweden (K2013-54X-03506-42-5)
  • Torsten Söderberg Foundation (M58/16)
  • Novo Nordisk Foundation (NNF16OC0021202)
  • ALF (ALFGBG-621581)
  • Swedish Diabetes Foundation (DIA2016-108)
  • Edgar Sjölund Foundation
  • WM Lundgren Foundation (2016-0935)
  • Gbg Diabetesförening (390/16)
  • EFSD/Lilly
  • Lisa och Johan Grönberg Foundation (2016-00087)
Topics
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
Keywords
subcutaneous adipose tissue, adipogenesis, adipose precursor cells, BMP4, GREM1, angiogenesis, lipolysis, free fatty acids, ectopic fat, insulin resistance, type 2 diabetes, epigenetic regulation
MeSH terms
Adipose Tissue, Animals, Cell Differentiation, Diabetes Mellitus, Type 2, Humans, Inflammation, Insulin Resistance, Obesity, Adipocytes, Adipogenesis

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